Therapeutic Monoclonal Antibodies

The approval of zolbetuximab (Vyloy) was a long time coming – a first-in-class therapy targeting a novel mechanism in gastric and GEJ cancers But while the excitement was high, the real-world rollout has been more… measured Let’s break it down 👇 Zolbetuximab is a CLDN18.2 inhibitor – a novel target CLDN18.2 is a tight junction protein expressed almost exclusively in gastric mucosa. These proteins help hold cells together in the highly acidic stomach environment. Zolbetuximab is a chimeric IgG1 monoclonal antibody that binds to CLDN18.2 on tumor cells and initiates cell death through: 💥 Antibody-dependent cellular cytotoxicity (ADCC) 💥 Complement-dependent cytotoxicity (CDC) It was approved for CLDN18.2-positive gastric or GEJ adenocarcinoma based on the SPOTLIGHT and GLOW trials, both of which showed improvements in PFS and OS But, as always in oncology, details matter 💡 Let’s talk about the vomiting 🤮 We don’t see much vomiting these days, and especially not grade 3+ In the SPOTLIGHT trial (GLOW was similar) we saw: 16% with grade 3+ vomiting - that’s hospitalization 😳 Grade 3 anorexia is significant weight loss or malnutrition 😳 Why so much vomiting? It’s not classic CINV The pathophysiology isn’t fully understood, but it’s thought to induce a form of acute gastritis In cycle 1, vomiting typically begins ~48 minutes after the infusion starts so prep your nurses Zolbetuximab is now considered highly emetogenic and patients should receive robust prophylactic antiemetics, plus breakthrough options (especially early on) 💡 Let's talk about infusion reactions It's a chimeric antibody (part human, part mouse) so infusion reactions aren't surprising - Hypersensitivity reactions (including anaphylaxis): ~18% - Grade 3-4 reactions: ~2% - Infusion reactions (fever, chills, etc.): ~3% Because of this, a 2-hrobservation period is required post-infusion, and the initial dose is titrated: - Loading dose: 800 mg/m² - Start at 100 mg/m²/hr for 30–60 min - Increase to 200–265 mg/m²/hr if tolerated Subsequent doses depend on Q2W or Q3W schedules – so you’ll need to stay sharp on the math 💡 Let's talk about logistical headaches Infusion rates are listed in mg/m²/hr, which most commercial pumps can’t handle – you’ll need to convert manually, which introduces potential for dosing errors It also has a short stability window – the product is stable at room temp for only 6 hrs which is going to be tight, especially on day 1 when infusions are likely to be held for 🤮. Plan to compound close to hang time and anticipate delays. Zolbetuximab is a great reminder that even breakthrough therapies bring baggage 😅 --- 📌 Start fostering your growth in oncology pharmacy practice with the Oncology Insights Newsletter I’m the Kelley in KelleyCPharmD 👋 and I help pharmacists learn the complex world of oncology #LearnOncology #Pharmacists #OncologyPharmacists #ClinicalPearls #Oncology

I spent the weekend reading Chai Discovery's technical report on AI-designed therapeutic antibodies. Then I tried to poke holes in it. 88 full-length monoclonal antibodies designed computationally, with atomic-level structural accuracy (<2Å RMSD). The first GPCR agonist antibodies designed by AI. Therapeutic-grade developability on first iteration. Template-dependent design. Variable success rates (4-100%). Framework selection bias. Incomplete selectivity data. This is the most advanced computational antibody design capability demonstrated publicly. Template-dependent, yes. But functional full-length mAbs with atomic accuracy hasn't been done before. Full technical analysis (achievements, limitations, and industry implications): https://lnkd.in/g659i8eh #AntibodyDesign #DrugDiscovery #ProteinEngineering

#Scientists #created an #antibody that can #eradicate an #infection that affects 95% of the #global #population. The Epstein-Barr virus (EBV) is one of the world’s most pervasive pathogens, infecting nearly 95% of humans and persisting for life. While widely known for causing mononucleosis, EBV is also a primary driver of several cancers, including lymphomas, and has been linked to severe neurological and chronic conditions. Scientists at Fred Hutch Cancer Center have now achieved a significant breakthrough by developing human monoclonal antibodies designed to block the virus's entry into human immune cells. By targeting specific proteins the virus uses to attach and invade, this new approach has successfully prevented infection in advanced laboratory models, offering a potential solution to a decades-old medical challenge. This development is particularly critical for the more than 128,000 #Americans who undergo #organ or #bone #marrow #transplants #annually In these vulnerable patients, #EBV can #reactivate and #trigger #post-#transplant #lympho #proliferative #disorder, life-threatening form of #cancer with few preventative options. The researchers envision a future where high-risk individuals receive antibody infusions to neutralize the virus before it can cause harm. Although human clinical trials are the next necessary step, this discovery represents a major leap toward controlling a quietly dangerous virus that has eluded effective prevention since its discovery. #Source: #FredHutch #CancerCenter. (2026)

𝗢𝘃𝗲𝗿𝘃𝗶𝗲𝘄 𝗼𝗳 𝗖𝗟𝗗𝗡18.2 𝗮𝘀 𝗮 𝗖𝗹𝗶𝗻𝗶𝗰𝗮𝗹𝗹𝘆 𝗩𝗮𝗹𝗶𝗱𝗮𝘁𝗲𝗱 𝗧𝗮𝗿𝗴𝗲𝘁 - CLDN18.2, is a tight junction protein, has emerged as a promising therapeutic target in oncology - It is highly specific, with expression largely restricted to the gastric mucosa in healthy tissues, minimizing off-target effects - However, CLDN18.2 is abnormally activated in several cancers, including gastric, gastroesophageal junction (GEJ), pancreatic, and biliary tract tumors, making it an attractive target for precision oncology - The FDA approval of zolbetuximab (IMAB362), a monoclonal antibody targeting CLDN18.2, for gastric cancer marks a significant milestone, validating its therapeutic potential - Zolbetuximab exerts its effects through antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction of apoptosis, has de-risked CLDN18.2 as a target, boosting confidence among researchers and investors to pursue it further - The target’s surface expression and stability make it amenable to a wide range of therapeutic approaches, including monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), CAR-T therapies, and bispecific antibodies - Beyond gastric and GEJ cancers, CLDN18.2’s expression in pancreatic and biliary tract cancers opens opportunities for broader applications 𝗖𝗼𝗺𝗽𝗲𝘁𝗶𝘁𝗶𝘃𝗲 𝗟𝗮𝗻𝗱𝘀𝗰𝗮𝗽𝗲: 𝗠𝗼𝗻𝗼𝗰𝗹𝗼𝗻𝗮𝗹 𝗔𝗻𝘁𝗶𝗯𝗼𝗱𝗶𝗲𝘀 (𝗺𝗔𝗯𝘀): - Zolbetuximab (IMAB362, Astellas Pharma) remains the frontrunner, being the first FDA-approved therapy for CLDN18.2-positive gastric cancer - Others include TST001 (Transcenta) and SHR-A1904 (Jiangsu Hengrui), both in P3 trials 𝗔𝗻𝘁𝗶𝗯𝗼𝗱𝘆-𝗗𝗿𝘂𝗴 𝗖𝗼𝗻𝗷𝘂𝗴𝗮𝘁𝗲𝘀 (𝗔𝗗𝗖𝘀): ADCs are gaining traction, leveraging CLDN18.2's surface expression for targeted payload delivery Notable candidates include SKB315 (Kelun Biotech) and LM-302 (LaNova Medicines) 𝗖𝗔𝗥-𝗧 𝗧𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀: - CT041 (CARsgen) & TAC01-CLDN18.2 (Triumvira) are in P2, exploring gastric & pancreatic cancers 𝗕𝗶𝘀𝗽𝗲𝗰𝗶𝗳𝗶𝗰 𝗔𝗻𝘁𝗶𝗯𝗼𝗱𝗶𝗲𝘀: - Bispecifics like PM1032 (Biotheus) & AMG 910 (Amgen) are in P2 /P1, respectively, aiming to engage T-cells for enhanced anti-tumor activity in CLDN18.2-positive cancers Intelligience Opinion: CLDN18.2 has solidified its position as a clinically validated target in oncology, driven by its specificity, broad applicability. It is witnessing a mix of established players (Astellas, Transcenta) and emerging innovators (CARsgen, Biotheus) advancing diverse modalities. Recent deals highlight the industry’s commitment to this target, while the focus on diagnostics and combination strategies positions CLDN18.2 as a cornerstone of precision oncology in gastric and related cancers. As the field progresses, addressing resistance and optimizing therapeutic combinations will be key to unlocking CLDN18.2’s full potential Want customized research and CI deep dive in CLDN18.2, DM me!

Scientists are increasingly turning to antibody therapy as a new way to fight infectious diseases that mutate quickly, such as bird flu and HIV. Traditionally used in cancer and autoimmune treatments, monoclonal antibodies are now being designed to neutralize viruses that have so far outsmarted standard antivirals. These lab-made antibodies mimic the immune system’s natural defenses and can be engineered to bind tightly to viruses, blocking their ability to infect cells or replicate. For the H5N1 bird flu virus, researchers have developed an antibody that attacks both the virus itself and the receptors it uses to enter human cells. This dual-target approach, tested in cell experiments, neutralized multiple strains of bird flu more effectively than single-target antibodies. Teams in Hong Kong and New York are also mapping how H5N1 mutates, building antibody libraries that could adapt as the virus evolves. Similar antibody strategies are being explored to make future vaccines more resilient against shifting viruses like SARS-CoV-2. Meanwhile, antibody research is reshaping HIV treatment. Current antiretroviral drugs suppress the virus but can’t eliminate dormant reservoirs hiding in T cells. By attaching antibodies to mRNA-based molecules, scientists can guide them precisely to infected cells, reactivating hidden viruses so they can be destroyed. Early studies suggest antibody therapy may even train the immune system to control HIV without lifelong medication. Although these treatments remain costly and require intravenous delivery, they mark a turning point in infectious disease medicine — using the body’s own immune logic to outsmart some of the most persistent viruses known. Research Paper 📄 DOI: 10.1038/d41586-025-03540-4

Biogen Redefines #TfR1 Antibody Design: Monovalent vs. Bivalent? A new mAbs publication from Biogen, “Balancing brain exposure, pharmacokinetics and safety of transferrin receptor antibodies for delivery of neuro-therapeutics,” challenges long-held assumptions and provides one of the most comprehensive analyses of TfR1 antibodies to date. Using transferrin receptor 1 (TfR1) to shuttle therapeutics across the blood–brain barrier (BBB) has become a popular strategy, but two questions have long divided the field: 🔹High vs. low affinity? 🔹Monovalent vs. bivalent antibodies? Key Insights 🔹 BBB transport follows a bell-shaped curve: Optimal transcytosis occurs at moderate affinity (EC₅₀ ~1–50 nM). Too weak → poor binding. Too strong → lysosomal trapping. 🔹 Bivalent antibodies can work just as well as monovalent—and sometimes better. This overturns the traditional belief that only monovalent antibodies are suitable for BBB delivery. 🔹 Affinity and valency jointly determine safety. Weak-affinity bivalent antibodies showed lower reticulocyte depletion than monovalent ones with similar EC₅₀—an unexpected “valency paradox.” 🔹 In vivo validation: Weak-affinity bivalent antibodies persist longer in serum and brain, while high-affinity ones get rapidly cleared and trapped in neuronal lysosomes. Therapeutic Potential Biogen demonstrated successful brain delivery of two therapeutic modalities using optimized TfR1 antibodies: 🔹Bispecifics targeting TfR1 + BACE1: Effective reduction of β-amyloid in mouse brain. (Monovalent → higher peak exposure; bivalent → more sustained exposure.) 🔹TfR1–oligonucleotide conjugates: Efficient gene silencing, with monovalent formats performing best. Why It Matters This work offers a toolbox for designing safer, more efficient BBB delivery platforms and dispels the long-standing dogma that “monovalent is always better.” It opens the door for future TfR1-based therapeutics—potentially including Biogen’s next-generation bispecifics or antibody–siRNA conjugates. Reference: "Balancing brain exposure, pharmacokinetics and safety of transferrin receptor antibodies for delivery of neuro-therapeutics." mAbs. Vol. 17. No. 1. Taylor & Francis, 2025.

Glycosylation for Therapeutic Applications Glycosylation has become a focus for therapeutic applications, particularly in the development of biologics, where glycan structure significantly affects the efficacy, stability, and safety of therapeutic proteins. One of the most prominent examples is the production of monoclonal antibodies (mAbs), where glycosylation affects their functions, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). By optimizing glycosylation patterns, scientists can enhance the therapeutic activity of mAbs, making them more effective in treating cancer, autoimmune diseases, and infectious diseases. Glycoengineering is also making progress in vaccines. The development of glycosylated antigens could improve immune responses, leading to more effective vaccines. For example, glycan-based vaccines against bacterial pathogens target specific glycan structures on the bacterial surface, triggering a strong and targeted immune response. These glycan-modified vaccines have shown promise in preclinical and clinical trials. In enzyme replacement therapy (ERT) for lysosomal storage diseases, glycosylation is critical for delivering therapeutic enzymes to the correct cellular compartments. Modifying the glycosylation of these enzymes can enhance their uptake by cells, thereby improving therapeutic efficacy. Additionally, the potential of glycosylation in regenerative medicine is being explored, particularly in the development of glycosylated biomaterials that can promote tissue repair and regeneration. These innovations highlight the critical role of glycosylation in advancing therapeutic approaches and improving patient outcomes. Reference [1] Xueting Ren et al., International Journal of Biological Sciences 2024 (10.7150/ijbs.93806) [2] Peter Seeberger et al., Essentials of Glycobiology [Internet]. 4th edition 2022 (https://lnkd.in/emtsU2X3) #Glycosylation #Biologics #MonoclonalAntibodies #GlycoEngineering #Vaccines #EnzymeReplacementTherapy #RegenerativeMedicine #Therapeutics #Biopharmaceuticals #BiomedicalResearch